SmI2-mediated radical cross-couplings of α-hydroxylated aza-hemiacetals and N, S -acetals with α,β-unsaturated compounds: Asymmetric synthesis of (+)-hyacinthacine A2, (-)-uniflorine A, and (+)-7- epi -casuarine

Article abstract of DOI:10.1021/jo200600n

The SmI₂-mediated radical coupling reactions of β-hydroxylated pyrrolidine/piperidine aza-hemiacetals 8 and 9 and N,S-acetals 6 and 33 with α,β-unsaturated compounds are described. This method allows a rapid access to β-hydroxylated pyrrolidine

Full text of DOI:10.1021/jo200600n

ARTICLE
pubs.acs.org/joc
SmI2-Mediated Radical Cross-Couplings of r-Hydroxylated
Aza-hemiacetals and N,S-Acetals with R,β-Unsaturated Compounds:
Asymmetric Synthesis of (þ)-Hyacinthacine A2, (ꢀ)-Uniflorine A, and
(þ)-7-epi-Casuarine
Xue-Kui Liu,†,‡ Shi Qiu,† Yong-Gang Xiang,† Yuan-Ping Ruan,† Xiao Zheng,*,†,‡ and Pei-Qiang Huang*,†
†Department of Chemistry and The Key Laboratory for Chemical Biology of Fujian Province, College of Chemistry and Chemical
Engineering, and ‡Department of Pharmaceutical Sciences, Medical College, Xiamen University, Xiamen, Fujian 361005, P. R. China
S Supporting Information
b
ABSTRACT: The SmI2-mediated radical coupling reactions of
β-hydroxylated pyrrolidine/piperidine aza-hemiacetals 8 and 9
and N,S-acetals 6 and 33 with R,β-unsaturated compounds are
described. This method allows a rapid access to β-hydroxylated
pyrrolidines, piperidines, pyrrolizidinones, and indolizidinones.
Starting from N,S-acetal 33 and via a common intermediate 27,
the alkaloids hyacinthacine A2 (2), uniflorine A (3, 6-epi-casuarine), and the unnatural epimer 7-epi-casuarine (37) have been
synthesized in four and five steps with overall yields of 34%, 16%, and 13%, respectively. The radical mechanism of the coupling
reactions has been confirmed by controlled experiments, which also allowed deducing the anionic mechanism in the coupling
between N,S-acetal 6 and carbonyl compounds. This demonstrates that the mechanisms of these SmI2-mediated reactions are
switchable from Barbier-type anionic to radical by cooperative action of BF3 OEt2 and t-BuOH.
3
’ INTRODUCTION
The saturated β-hydroxylated N-containing heterocycles con-
stitute an important subclass of pharmaceutically relevant mol-
ecules and bioactive natural products.1,2 Polyhydroxylated
alkaloids (e.g., 1ꢀ5 in Figure 1), also known as azasugars and
iminosugars,2 exhibit potent inhibitory activity toward carbohy-
drate-processing enzymes and are particularly promising for the
development of drugs against metabolite-disorder-associated
diseases.2
The key reaction for the synthesis of this kind of molecule is
the carbonꢀcarbon bond formation at the N-R-carbon, which
has attracted considerable attention of many organic synthetic
chemists.3ꢀ6 The radical-based coupling methods5 are unique
Figure 1. Some polyhydroxylated alkaloids.
and complementary to those based on the carbocations
(iminium ions) (route 1 in Scheme 1),3 umpoled N-acyl-
carbanions (route 2 in Scheme 1),4 and organometallic
intermediates.6 The classical radical reactions generally required
the use of highly toxic tin reagents and carcinogenic benzene as
the solvent. Thanks to the pioneering work of Kagan on the
chemistry of samarium diiodide,7 the use of SmI2 as a versatile
single electron reducing agent has opened a new avenue for
radical chemistry8 and is a basis for the development of new
carbonꢀcarbon bond formation methods at the N-R-carbon.9
Previously, we have developed a SmI2-mediated Barbier-type
reductive coupling of N,S-acetal 6 with carbonyl compounds
(Scheme 2), which was assumed to proceed through an
organosamarium(III) intermediate, namely, via the anionic route
2 shown in Scheme 1.10
With the dual aims to, on one hand, develop a complementary
radical-based method and, on the other hand, explore the
possibility to use aza-hemiacetals/ N,S-acetals as precursors of
R-aminoalkyl radicals, we decided to develop the chemistry
outlined by route 3 in Scheme 1, and the preliminary results
have been reported in a recent communication.11 In order to
widen the scope of this method, we decided to investigate the
coupling reactions of β-hydroxylated pyrrolidine/piperidine aza-
hemiacetals 8/9 with R,β-unsaturated compounds (Figure 2).
The use of aza-hemiacetals as the synthetic equivalents of radical
Received: March 23, 2011
Published: May 16, 2011
r
2011 American Chemical Society
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Scheme 1. Three Types of CarbonꢀCarbon Bond Forma-
tion Methods at the N-R-Carbon
Figure 2. Plausible synthetic equivalents of β-hydroxylated pyrroli-
dine/piperidine N-R-radical synthons as alternatives to the correspond-
ing N-R-carbanion synthons.
Table 1. Results on the SmI2-Mediated Radical Coupling
Reaction of r-Silyloxy N,S-Acetal 6 with Ethyl Acrylate
Scheme 2
% yielda
of 10a (dr)b
additive
T (°C)
% yielda of 11
synthons A would provide an alternative to overcome the
difficulties encountered in the generation and reaction of carba-
nion synthons B,12 which is challenging yet quite attractive for
the synthesis of azasugars.10,12 In this paper, we report the full
details of this study, which also include the confirmation of the
radical mechanism, and the application of the newly developed
method to the asymmetric synthesis of the alkaloids hyacintha-
cine A2 (2), uniflorine A (3), and the unnatural epimer (þ)-7-
epi-casuarine (37).
1
2
3
4
none
rt
0
none
35
59
65
15
t-BuOH (4.0 equiv)
24 (87:13)
trace
BF3 OEt2 (2.0 equiv)
ꢀ78
ꢀ78
3
BF3 OEt2 (2.0 equiv)/
60 (87:13)
3
t-BuOH (4.0 equiv)
a Isolated yield. b Determined by HPLC analysis.
Scheme 3. Mechanistic Study on the SmI2-Mediated Cou-
pling Reactions between N,S-Acetal 6 and Ethyl Acrylate/
Cyclohexanone
’ RESULTS AND DISCUSSION
SmI2-Mediated Coupling Reaction of r-Silyloxy N,S-Acetal 6
with Ethyl Acrylate. As a model study, the coupling of the
known N,S-acetal 610a with ethyl acrylate was first investigated
under the conditions previously defined for the reductive cou-
pling of 6 with carbonyl compounds.10a Treatment of N,S-acetal
6 and ethyl acrylate with SmI2 led only to the reduced product 11
in 35% yield (Table 1, entry 1). When 4.0 equiv of tert-butanol
was used as an additive, the desired product 10a was obtained in
24% yield (Table 1, entry 2), while use of BF3 OEt2 (2.0 equiv)
3
as an additive afforded only the reduced product 11 in 65% yield
(Table 1, entry 3). To our delight, in the presence of both
BF3 OEt2 (2.0 equiv) and tert-butanol (4.0 equiv), the desired
3
product 10a was obtained in 60% yield as a diastereomeric
mixture (dr = 87: 13), along with the reduced product 11 in 15%
yield (Table 1, entry 4).
Mechanism for the SmI2-Mediated Coupling Reactions
between N,S-Acetal 6 and Ethyl Acrylate. To probe the
mechanism of the coupling reaction, N,S-acetal 6 and cyclohex-
anone were subjected to the coupling conditions indicated in
Table 1, entry 4; however, only the reduced product 11 was
obtained in 61% yield (Scheme 3, a). The reaction of N,S-acetal 6
with a mixture of cyclohexanone and ethyl acrylate led to the
formation of compound 10a and the reduced product 11 in 62%
and 15% yields, respectively (Scheme 3, b). The coupling
product (12) of N,S-acetal 6 with cyclohexanone was obtained
in 63% yield only in the absence of both Lewis acid and proton
source, namely, under the conditions we previously established
for the Barbier-type reactions (Scheme 2 and Scheme 3, c).10a
Based on these results, it could be concluded that in the presence
of both a Lewis acid (BF3 OEt2)13 and a proton source
3
(t-BuOH)14 the coupling reaction between N,S-acetal 6 and an
R,β-unsaturated compound proceeds through a radical mecha-
nism (cf. Scheme 4). These results also allowed deducing the
anionic mechanism in the coupling between N,S-acetal 6
and carbonyl compounds.10a Thus, the complementary mechan-
isms of these SmI2-mediated reactions are switchable from
Barbier-type anionic to radical by use of both BF3 OEt2 and
3
t-BuOH as additives.
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Scheme 4. Plausible Main Mechanism for the SmI2-
Mediated Coupling Reactions of N,S(O)-Acetals/Aza-hemi-
acetals 13 with R,β-Unsaturated Compounds
Table 2. SmI2-Mediated Cross-Coupling Reactions of the
Aza-hemiacetals 8/9 with R,β-Unsaturated Compounds
With the radical nature of the reaction confirmed, a general-
ized mechanism for the SmI2-mediated coupling reactions
between N,S(O)-acetals/aza-hemiacetals 13 and R,β-unsatu-
rated compounds was proposed in Scheme 4. In the presence
of a Lewis acid (such as BF3 OEt2), the N-acyliminium ion C is
3
generated from N,S(O)-acetals/aza-hemiacetals 13, which is
reduced by SmI2 to give the R-acylaminoalkyl radical intermedi-
ate D.9a,h,15 The radical D is trapped by an R,β-unsaturated
compound, and the resultant radical receives a second electron
from SmI2 to produce the samarium(III) salt E that is quenched
by t-BuOH to give the cross-coupling product 14.14 It is worthy
to mention that on account of the result displayed in Table 2,
entry 2, a partial generation of R-acylaminoalkyl radical inter-
mediate D by SmI2-mediated direct homocleavage of the CꢀS
bond16 could not be excluded.
The formation of the R-acylaminoalkyl radical intermediate
D via N-acyliminium ion (C) was proven by the coupling
reactions of aza-hemiacetals/ N,O-acetals 15 with R,β-unsatu-
rated compounds to give 16 (Scheme 5, a).11 The radical mech-
anism was also confirmed by the isolation of dimeric product
19 from the homocoupling of aza-hemiacetal 18 in the absence of
an R,β-unsaturated compound (Scheme 5, b).11 Considering the
ready availability of both aza-hemiacetals and N,O-acetals by
numerous methods,3,17 it is of great synthetic value that they can
be used as general precursors of N-R carbon radicals.
a Only the major diastereomer shown. b Isolated yield. c Determined
by HPLC. d Determined by chromatographic separation.
SmI2-Mediated Coupling Reactions of r-Hydroxylated
Aza-hemiacetals with r,β-Unsaturated Compounds. We
next investigated the coupling of R-hydroxylated aza-hemiacetals
with R,β-unsaturated compounds. The synthesis of the β-hydro-
xylated pyrrolidine aza-hemiacetal (S)-8 (cf. Figure 2) has been
reported previously.10a The aza-hemiacetal 9 was synthesized as a
separable 1:1 diastereomeric mixture by a regioselective reduction
(DIBAL-H, CH2Cl2, ꢀ78 °C) of the known activated lactam (S)-
2012d,e (Scheme 6).
two diastereomers (10c) in 76:24 ratio with 64% combined yield
(Table 2, entry 3). Compared with the pyrrolidine aza-hemi-
acetal 8, the couplings of the piperidine aza-hemiacetal 9 with
ethyl acrylate and acrylonitrile produced the corresponding
products 21a and 21b in similar yields but with lower diastereos-
electivities (Table 2, entries 4 and 5). The stereochemistry of
major diastereomers was assumed to be trans in light of the
literature precedents,18 which was confirmed by converting
products 10a and 21a into the known compounds, respectively
(vide infra).
The cross-coupling reaction of the chiral aza-hemiacetal 8 with
R,β-unsaturated compounds was first investigated. Treatment of
aza-hemiacetal 8 and ethyl acrylate with BF3 OEt2 and a freshly
3
prepared t-BuOH-containing SmI2 solution in THF at ꢀ40 °C
for 10 min produced the desired coupling product 10a as a trans/
cis diastereomeric mixture in 89:11 ratio (combined yield 72%),
along with the reduced product 11 in 9% yield (Table 2, entry 1).
The cross-coupling reaction with ethyl R-methylacrylate
gave 10b as a mixture of three diastereomers in a ratio of
50:39:11 (Table 2, entry 2), which implicated that trans/cis
diastereoselectivity was 89:11, and the diastereomeric ratio at
C-20 was 56:44. The coupling with more active acrylonitrile gave
Synthesis of 1-Hydroxypyrrolizidine (1S,7aR)-25 and
8-Hydroxyindolizidinone (8S,8aR)-26. With dual aims to con-
firm the stereochemistry of the coupling products and to
demonstrate the applicability of the method, the coupling
products 10a and 21a were converted into 1-hydroxypyrrolizi-
dine (1S,7aR)-25 and 8-hydroxyindolizidinone (8S,8aR)-26,
respectively. Successive treatment of the diastereomeric mixture
10a and 2-epi-10a with a solution of 2 N HCl in EtOAc and
K2CO3 in EtOH/H2O yielded the pyrrolizidinone 23a/23b
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Scheme 5
Scheme 7. Synthesis of 1-Hydroxypyrrolizidine (1S,7aR)-25
Scheme 6. Preparation of Aza-hemiacetal 9
Scheme 8. Synthesis of 8-Hydroxyindolizidinone (8S,8aR)-
26
(dr = 88:12) as an inseparable diastereomeric mixture (Scheme 7).
After silylation, the two diastereomers 24a and 24b (dr = 91:9)
were separated. The minor diastereomer (7S,7aS)-24b is iden-
tical to a known compound, which has served as a key inter-
mediate for the asymmetric synthesis of the necine base (ꢀ)-
supinidine.19 The major diastereomer 24a was deprotected
by treatment with a solution of 2 N HCl in EtOAc, and pure
pyrrolizidinone 23a was reduced with LiAlH4 to afford
(1S,7aR)-1-hydroxypyrrolizidine 25 in 56% yield over two steps
{[R]20 þ23.5 (c 0.6, CHCl3); lit.20a [R]20 ꢀ26 (c 2.3,
Scheme 9. Retrosynthetic Analysis of Hyacinthacine A2 and
Uniflorine A
D
D
CHC13) for the antipode}.
Successive treatment of the major diastereomer 21a with 2 N
HCl and K2CO3 led to the formation of the 8-hydroxyindolizi-
dinone (8S,8aR)-26 in 52% yield (Scheme 8).21 The spectral data
of the synthetic products 25 and 26 were in agreement with those
reported.20,21 Thus the cross-coupling reaction is confirmed to
be 2,3-trans-diastereoselective. It is worth mentioning that the O-
TBS-protected derivative of 26 and its enantiomer have been
used as the key intermediates for the asymmetric syntheses of
(ꢀ)-swainsonine22b and its analogues.22a
Attempted Asymmetric Synthesis of (þ)-Hyacinthacine
A2 (2) and (ꢀ)-Uniflorine A (3). To further demonstrate the
scope and synthetic value of the method, the syntheses of the
polyhydroxylated pyrrolizidine alkaloids hyacinthacine A2 (2)
and uniflorine A (3) were envisioned. Hyacinthacine A2,23,24
isolated along with hyacinthacines A1, A3, and B2 from the bulbs
of Muscari armeniacum (Hyacinthaceae), exhibited selective
inhibitory activity against amyloglucosidase (Aspergillus niger)
with an IC50 of 8.6 μM.23 (ꢀ)-Uniflorines A and B,25ꢀ27 were
isolated from the leaves of the Paraguayan tree Eugenia uniflora L,
which has been used as a traditional antidiabetic agent in
Paraguay for a long time. As an inhibitor of the R-glucosidases,
uniflorine A showed inhibitory activities against rat intestinal
maltase and sucrase with IC50's of 12 and 3.1 μM, respectively.25
The originally assigned structure for (ꢀ)-uniflorine A has been
revised to that shown in Figure 1,26 while uniflorine B turned
out to share the same structure as casuarine,28,29 another azasugar
isolated from the bark of Casuarina equisetfolia L. (Casuarinaceae).28
Due to their significant bioactivities and intriguing structural
features, the syntheses of both hyacinthacine A224 and (ꢀ)-uni-
florine A26,27 have attracted much attention. Our retrosynthetic
analyses of hyacinthacine A2 (2) and uniflorine A (3) are shown
in Scheme 9, which features, first, the use of the hydroxylated
pyrrolizidinone derivative 27 as a common intermediate and,
second, the formation of tetrasubstituted pyrrolidine 29 via the
key SmI2-mediated radical cross-coupling reaction of the aza-
hemiacetal 30 with ethyl acrylate.
The synthesis started with the known activated amide 31,
which was obtained by reductive benzyloxymethylation of a
protected (R,R)-tartarimide.30 Treatment of compound 31 with
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Scheme 10
Scheme 12. Asymmetric Synthesis of (þ)-Hyacinthacine A2
assumed to be 4,5-trans, which was confirmed by conversion
into the natural products hyacinthacine A2 and uniflorine A (vide
infra).
Scheme 11
According to the experiments, N,S-acetal 33 can generate the
R-acylaminoalkyl radical intermediate at a lower temperature
(ꢀ60 °C) than aza-hemiacetal 30 (ꢀ40 °C). The different
reactivity between N,S-acetal 33 and aza-hemiacetal 30 may
be due to the stability of the same radical intermediate under
different temperature. At ꢀ60 °C, the radical intermediate is
stable enough to be captured by ethyl acrylate, but at ꢀ40 °C, the
radical intermediate is able to be further reduced by SmI2 to
generate a carbanion, followed by protonation to provide the
reduced product 32.
Cleavage of the N-Boc group in urethane pyrrolidine 29 with a
solution of 2 N HCl in EtOAc, followed by K2CO3-promoted
cyclization gave the pyrrolizidinone 2724d in 87% yield over two
steps (Scheme 12). Reduction of compound 27 with LiAlH4
in THF gave the known pyrrolizidine derivative 3424b,d,h in
79% yield. The stereochemistry of 34 was established by analysis
of NOESY spectrum (cf. Supporting Information) to be
1R,2R,3R,7aR.
NaBH4 at ꢀ10 °C produced a diastereomeric mixture of aza-
hemiacetal 30 in 98% yield. Unfortunately, the SmI2-mediated
cross-coupling of aza-hemiacetal 30 with ethyl acrylate was
unsuccessful; only the reduced product 32 was obtained in
60% yield (Scheme 10). The different reactivity between aza-
hemiacetal 30 and 8 may be due to the effects of the substituent
on the pyrrolidine ring. The R-acylaminoalkyl radical intermedi-
ates generated from more substituted pyrrolidine aza-hemiacetal
are less reactive toward R,β-unsaturated compounds (e.g., ethyl
acrylate), which were further reduced by SmI2 to yield the
reduced product. This is evident from the yields of cross-
coupling products/reduced product that change from 76%/0
for unsubstituted pyrrolidine aza-hemiacetal 18,11 to 72%/9% for
monosubstituted pyrrolidine aza-hemiacetal 8 (Table 2, entry 1),
and 0/60% for trisubstituted pyrrolidine aza-hemiacetal 30.
Compound 32 is a fully protected form of 1,4-dideoxy-1,4-
imino-D-arabinitol (1, known as DAB 1), which was isolated
from two types of leguminose plants, Arachniodes standishii31a,b
and Angylocalyx boutiqueanus.31c
Finally, tris-O-debenzylation of pyrrolizidine 34 by catalytic
hydrogenolysis in acidic medium (H2, 10% Pd/C, 6 N HCl, rt)
followed by neutralization (DOWEX OHꢀ form) provided
hyacinthacine A2 (2) in 81% yield {[R]20 þ10.6 (c 1.2,
D
H2O); lit.24c [R]20 þ10.5 (c 0.6, H2O)} (Scheme 12). The
D
spectral data of the synthetic hyacinthacine A2 (1) matched those
reported.23,24
Asymmetric Synthesis of (ꢀ)-Uniflorine A (3) and (þ)-7-
epi-Casuarine (37). For the synthesis of uniflorine A (3),
compound 27 was successively treated with LDA (2.4 equiv)
and PhSeBr (1.1 equiv) to yield the phenylselenylated product,
which without separation was subjected to the oxidative elimina-
tion (H2O2, CH2Cl2, rt)32 to produce the R,β-unsaturated
indolizidinone 28 in 71% overall yield, along with 10% of the
recovered starting material 27 (Scheme 13).
For the diastereoselective dihydroxylation of R,β-unsaturated
lactam 28, several conditions have been tried (cf. Supporting
Information). It was found that treatment of compound 28 with
OsO4/NMO in a mixed solvent system of t-BuOH/H2O
(v/v 1:1) and in the presence of citric acid33 produced poly-
hydroxylated pyrrolizidinones 35 and its diastereomer 36 (dr =
60:40) as a separable diastereomeric mixture in a combined yield
of 93%, whereas treatment of compound 28 with KMnO4/
18-crown-634 at ꢀ10 °C produced diastereomers 35 and 36 in
a reversed 14:86 ratio with a combined yield of 64% (Scheme 13).
Asymmetric Synthesis of (þ)-Hyacinthacine A2 (2). The
failure in the radical coupling of aza-hemiacetal 30 with ethyl
acrylate led us to envision the use of N,S-acetal 33 as a more
reactive substrate. The requisite N,S-acetal 33 was prepared by
reaction of the aza-hemiacetal 30 with 2-mercaptopyridine
(CaCl2, BF3 Et2O, CH2Cl2) as a separable diastereomeric
3
mixture in 70:30 ratio with 85% yield (Scheme 11). The SmI2-
mediated radical coupling of the diastereomeric mixture of
N,S-acetal 33 with ethyl acrylate at ꢀ60 °C went smoothly to
produce the desired product 29 as a single diastereomer in
61% yield, along with the fully reduced product 32 in 30%
yield. The stereochemistry of the coupling product 29 was
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Scheme 13. Asymmetric Synthesis of (ꢀ)-Uniflorine A (3)
and (þ)-7-epi-Casuarine (37)
’ CONCLUSIONS
In conclusion, we have demonstrated that under appropriate
conditions (SmI2, BF3 OEt2, t-BuOH), aza-hemiacetals/N,
3
O-acetals 15, aza-hemiacetals 8, 9, and N,S-acetals 6, 33 can
serve as valuable synthetic equivalents of the corresponding
R-aminoalkyl radical synthons, in particular β-hydroxylated
pyrrolidine/piperidine R-radical synthons A. The one-pot radical
coupling reactions of 8, 9, 6, and 33 with R,β-unsaturated
compounds overcome the challenges associated with the valida-
tion of the corresponding β-hydroxylated pyrrolidine/piperidine
N-R carbanions (B). The coupling reactions have been shown to
be 2,3-trans-diastereoselective. The method provides a ready
access to β-hydroxylated pyrrolidines, piperidines, pyrrolizidi-
none, and indolizidinone systems. From N,S-acetal 33, the poly-
hydroxylated pyrrolizidine alkaloids hyacinthacine A2 (2),
uniflorine A (3, 6-epi-casuarine), and the unnatural epimer 7-epi-
casuarine (37) have been synthesized in four and five steps with
overallyieldsof34%, 16%, and 13%, respectively. The formationof
the fully protected form of DAB 1 (32) implies that the SmI2-
mediated reaction may be used as an alternative method for the
reductive dehydroxylation of aza-hemiacetals.12c,36 This metho-
dology is also applicable to the synthesis of other pyrrolizidine
alkaloids and their diastereomers.
’ EXPERIMENTAL SECTION
General Procedure for the Cross-Coupling of Aza-hemi-
acetals 8/9 with R,β-Unsaturated Compounds. To a slurry of
Sm powder (flame-dried under Ar, 826 mg, 5.5 mmol) in anhydrous
THF (50 mL) was added I2 (1.27 g, 5.0 mmol) at room temperature
under an argon atmosphere. The reaction mixture was stirred for 2 h at
45 °C to yield a SmI2 (0.1 N in THF) reagent. To the resulting mixture
was added t-BuOH (0.43 mL, 5.0 mmol), and the mixture was stirred for
10 min to yield a t-BuOH-containing SmI2 (both 0.1 N in THF).
To a solution of an aza-hemiacetal (8 or 9) (0.50 mmol), an R,
Figure 3. Conformation of R,β-unsaturated pyrrolizidinone 28.
β-unsaturated compound (1.0 mmol), and BF3 Et2O (1.0 mmol) in
3
The stereochemistry of diastereomer 35 was established via
NOESY spectrum of its bisacetyl derivative 38 (cf. Supporting
Information).
anhydrous THF (10 mL) was added dropwise a freshly prepared
t-BuOH-containing SmI2 (both 0.1 N in THF, 20 mL, 2.0 mmol)
at ꢀ40 °C under an argon atmosphere. The reaction mixture was stirred
for 10 min and quenched with a saturated aqueous solution of NH4Cl
(10 mL). The mixture was extracted with EtOAc (3 ꢁ 15 mL), and the
combined organic phases were washed with brine, dried over anhydrous
Na2SO4, filtered, and concentrated under reduced pressure. The residue
was purified by flash chromatography on silica gel to afford the desired
cross-coupling product. In some cases, the reduced product was isolated
as a byproduct.
The different face-selectivity observed in the dihydroxylation
of R,β-unsaturated lactam 28 with different oxidation methods
can be understood on the basis of the conformation shown in
Figure 3. The concave face is somewhat sterically more con-
gested, and thus the osmylation occurred more preferentially
from the convex face (dr = 60:40, combined yield 93%). With
sterically more hindered dihydroxylation reagent system KMnO4/
18-crown-6, severe interaction with H-7a and the benzyloxy group
became a predominating fact that prevented an attack on the
convex face. A concave face attack thus occurred to give indolizi-
dinone 36 as the major diastereomer but in a much lower yield
(dr = 14:86, combined yield 64%).
(2R/S,3S)-3-tert-Butyldimethylsilyloxy-1-tert-butyloxycar-
bonyl-2-[(2-ethyloxycarbonyl)ethyl]pyrrolidine (10a and
2-epi-10a). Cross-Coupling of N,S-Acetal 6 with Ethyl Acrylate. To
a solution of N,S-acetal 6 (205 mg, 0.50 mmol), ethyl acrylate (0.11 mL,
1.0 mmol), and BF3 Et2O (0.12 mL, 1.0 mmol) in anhydrous THF
3
(10 mL) was added dropwise a freshly prepared t-BuOH-containing
SmI2 (both 0.1 N in THF, 20 mL, 2.0 mmol) at ꢀ78 °C under an argon
atmosphere. The reaction mixture was stirred for 30 min and quenched
with a saturated aqueous solution of NH4Cl (10 mL). The mixture was
extracted with EtOAc (3 ꢁ 15 mL), and the combined organic phases
were washed with brine, dried over anhydrous Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified by flash
chromatography on silica gel to afford 10a and 2-epi-10a as an insepar-
able mixture (dr = 87:13, determined by HPLC) in a combined yield of
60% and the reduced product 11 in 15% yield.
To complete the synthesis of (ꢀ)-uniflorine A (3), diaster-
eomer 35 was reduced with LiAlH4, and the resulting product
was tris-O-debenzylated (H2, PdCl2, rt) to give the desired
polyhydroxylated pyrrolizidine (ꢀ)-uniflorine A (3) in 78%
yield over two steps (Scheme 13). The optical rotation
{[R]20 ꢀ6.7 (c 0.42, H2O); lit.27b [R]D ꢀ6.9 (c 0.415,
21
D
H2O)} and spectral data of the synthetic uniflorine A (3)
matched those reported.27a Following the same procedure,
diastereomer 36 was converted into 7-epi-casuarine (37)35
{[R]20 þ6.1 (c 0.62, H2O); lit.35 [R]D þ6.2 (c 0.65, H2O)}
22
Cross-Coupling of Aza-hemiacetal 8 with Ethyl Acrylate. Following
the general procedure, the SmI2-mediated coupling reaction of aza-hemiacetal
D
in 64% yield over two steps.
4957
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ARTICLE
8 with ethyl acrylate afforded 10a and 2-epi-10a as an inseparable
mixture [dr = 89:11, determined by HPLC: Shim-pack VP-ODS (150 ꢁ
4.6), CH3CN/H2O 70:30, 1.0 mL/min, λ = 254 nm, t1 = 8.8 min
(88.8%), t2 = 14.7 min (11.2%)] in a combined yield of 72%, and the
reduced product 11 in 9% yield. Mixture of 10a and 2-epi-10a: colorless
oil; IR (film) vmax 2956, 2930, 2858, 1736, 1697, 1391 cmꢀ1. 1H NMR
(400 MHz, CDCl3) δ 0.03 (s, 6H), 0.83 and 0.87 (2s br, 9H), 1.18ꢀ1.28
(m, 3H), 1.43 (s, 9H), 1.56ꢀ2.06 (m, 4H), 2.24ꢀ2.50 (m, 2H),
3.24ꢀ3.35 (m, 1H), 3.36ꢀ3.76 (m, 2H), 3.98ꢀ4.05 (m, 1H),
4.05ꢀ4.17 (m, 2H); 13C NMR (100 MHz, CDCl3) δ ꢀ4.8, 14.2,
17.9, 18.0, 25.6, 25.7, 28.4, 31.1, 31.4, 31.9, 32.6, 44.0, 44.5, 60.4, 65.8,
74.8, 75.6, 78.9, 79.3, 155.3, 173.1, 173.3. MS (ESI, m/z): 424 (M þ
Naþ). HRESIMS calcd for [C20H39NO5SiNa]þ (M þ Naþ): 424.2489;
found: 424.2485.
(t, J = 7.1 Hz, 3H), 1.42 (s, 9H), 1.50ꢀ1.74 (m, 4H), 1.82ꢀ1.97
(m, 2H), 2.25ꢀ2.32 (m, 2H), 2.52ꢀ2.84 (m, 1H), 3.64ꢀ3.72 (m, 1H),
3.84ꢀ4.20 (m, 2H), 4.13 (q, J = 7.1 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ ꢀ5.03, ꢀ5.01, 14.2, 18.0, 19.2, 24.0, 25.7 (3C), 27.2, 28.4
(3C), 30.9, 37.9, 57.1, 60.4, 68.2, 79.1, 155.6, 173.2. MS (ESI, m/z): 438
(M þ Naþ, 100), 454 (M þ Kþ, 68), 416 (M þ Hþ, 56). Anal. Calcd for
C21H41NO5Si: C, 60.68; H, 9.94; N, 3.37. Found: C, 60.69; H, 9.98;
N, 3.45.
2-epi-21a (minor diastereomer): colorless oil; [R]20 þ19.9 (c
D
1.1, CHCl3). IR (film) vmax 2951, 2932, 2857, 1736, 1696, 1417, 1364,
1252 cmꢀ1. 1H NMR (400 MHz, CDCl3) δ 0.06 and 0.07 (2s br, 6H), 0.89
(s, 9H), 1.24 (t, J = 7.1 Hz, 3H), 1.44 (s, 9H), 1.47ꢀ1.70 (m, 4H),
1.78ꢀ1.91 (m, 1H), 1.94ꢀ2.06 (m, 1H), 2.15ꢀ2.40 (m, 2H), 2.53ꢀ2.75
(m, 1H), 3.61ꢀ3.73 (m, 1H), 3.74ꢀ4.00 (m, 1H), 4.05ꢀ4.35 (m, 1H),
4.12 (q, J = 7.1 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ ꢀ4.9, 14.2, 18.1
and 18.5, 24.2, 25.8 (3C), 28.4 (3C), 30.9 and 31.0, 36.6, 38.1, 54.7
and 56.1, 60.3, 69.5 and 70.0, 79.6, 155.0, 173.4. MS (ESI, m/z): 438
(M þ Naþ, 100).
(2R/S,3S,20R/S)-3-tert-Butyldimethylsilyloxy-1-tert-butyloxy-
carbonyl-2-(2-ethyloxycarbonyl)propylpyrrolidine (10b). Fol-
lowing the general procedure, the SmI2-mediated coupling reaction of
aza-hemiacetal 8 with ethyl R-methacrylate afforded compound 10b as
an inseparable diastereomeric mixture [dr = 50:39:11, determined by
HPLC: Shim-pack VP-ODS (150 ꢁ 4.6), CH3CN/H2O 75:25, 1.0 mL/
min, λ = 254 nm, t1 = 24.4 min (50%), t2 = 25.6 min (39%), t3 = 30.6 min
(11%)] in a combined yield of 72% as a colorless oil and reduced product
11 in 9% yield. 10b: IR (film) vmax 2956, 2932, 2858, 1734, 1698, 1392,
(2R/S,3S)-3-tert-Butyldimethylsilyloxy-1-tert-butyloxycar-
bonyl-2-(2-cyanoethyl)piperidine (21b and 2-epi-21b). Fol-
lowing the general procedure, the SmI2-mediated coupling reaction of
aza-hemiacetal 9 with acrylonitrile afforded compound 21b (yield 32%)
and its diastereomer 2-epi-21b (yield 30%) (dr = 52:48). 21b (more
polar diastereomer): colorless oil; [R]20D ꢀ1.5 (c 1.0, CHCl3). IR (film)
vmax 2954, 2930, 2857, 2244, 1690, 1419, 1366, 1251 cmꢀ1. 1H NMR
(400 MHz, CDCl3) δ 0.03 and 0.06 (2s br, 6H), 0.87 (s, 9H), 1.26ꢀ1.36
(m, 1H), 1.45 (s, 9H), 1.56ꢀ1.71 (m, 3H), 1.83ꢀ2.03 (m, 2H),
2.21ꢀ2.39 (m, 2H), 2.56ꢀ2.78 (m, 1H), 3.65ꢀ3.71 (m, 1H),
3.96ꢀ4.30 (m, 2H); 13C NMR (100 MHz, CDCl3) δ ꢀ5.05, ꢀ4.98,
14.2, 17.9, 19.0, 25.1, 25.7 (3C), 27.3, 28.1, and 28.3 (3C), 38.2, 56.7,
67.9, 79.8, 119.4, 155.5. MS (ESI, m/z): 391 (M þ Naþ, 100). Anal.
Calcd for C19H36N2O3Si: C, 61.91; H, 9.84; N, 7.60. Found: C, 61.91;
H, 10.07; N, 7.87.
1
1254 cmꢀ1. H NMR (400 MHz, CDCl3) (diastereomeric mixture)
δ 0.01ꢀ0.07 (m, 6H), 0.80ꢀ0.89 (m, 9H), 1.15ꢀ1.26 (m, 6H),
1.40ꢀ1.46 (m, 9H), 1.46ꢀ2.01 (m, 4H), 2.38ꢀ2.70 (m, 1H),
3.14ꢀ3.84 (m, 3H), 3.93ꢀ4.32 (m, 3H); 13C NMR (100 MHz, CDCl3)
(diastereomeric mixture) δ ꢀ5.1, ꢀ4.8, 14.1, 14.2, 17.5, 17.7, 17.8, 18.0,
25.6, 25.7 (3C), 28.5 (3C), 31.8, 32.6, 36.5, 36.9, 37.3, 43.8, 44.4, 60.2,
64.4, 64.8, 75.6, 75.8, 78.8, 79.3, 155.1, 155.4, 176.2. MS (ESI, m/z): 438
(M þ Naþ, 100). Anal. Calcd for C21H41NO5Si: C, 60.68; H, 9.94;
N, 3.37. Found: C, 60.70; H, 9.86; N, 3.63.
(2R/S,3S)-3-tert-Butyldimethylsilyloxy-1-tert-butyloxycar-
bonyl-2-(2-cyanoethyl)pyrrolidine (10c and 2-epi-10c). Fol-
lowing the general procedure, the SmI2-mediated coupling reaction of
aza-hemiacetal 8 with acrylonitrile afforded compound 10c (yield 47%),
its diastereomer 2-epi-10c (yield 17%) (dr = 74:26), and reduced
product 11 in 5% yield. 10c (major diastereomer): colorless oil;
2-epi-21b (less polar diastereomer): colorless oil; [R]20D þ7.8 (c 0.9,
CHCl3). IR (film) vmax 2954, 2932, 2859, 2244, 1695, 1413, 1366,
1253 cmꢀ1
.
1H NMR (400 MHz, CDCl3) δ 0.02ꢀ0.12 (m, 6H),
0.81ꢀ0.92 (m, 9H), 1.38ꢀ1.54 (m, 11H), 1.55ꢀ1.71 (m, 2H), 1.78ꢀ
1.92 (m, 1H), 1.98ꢀ2.14 (m, 1H), 2.16ꢀ2.42 (m, 2H), 2.44ꢀ2.72 (m,
1H), 3.64ꢀ3.74 (m, 1H), 3.80ꢀ4.10 (m, 1H), 4.17ꢀ4.40 (m, 1H);
13C NMR (100 MHz, CDCl3) δ ꢀ4.9, ꢀ4.7, 14.1 and 14.2, 18.0, 19.9
and 20.3, 24.0 and 24.2, 25.7 (3C), 28.3 and 28.5 (3C), 28.7, 36.7 and 38.3,
54.6 and 55.4, 69.4 and 69.5, 80.0 and 80.3, 119.4 and 120.0, 154.8. MS (ESI,
m/z): 391 (M þ Naþ, 100). Anal. Calcd for C19H36N2O3Si: C, 61.91; H,
9.84; N, 7.60. Found: C, 61.72; H, 10.12; N, 7.92.
[R]20 ꢀ0.3 (c 1.3, CHCl3). IR (film) vmax 2956, 2931, 2858, 2244,
D
1694, 1392, 1366 cmꢀ1. 1H NMR (400 MHz, CDCl3) δ 0.03 and 0.04
(2s br, 6H), 0.83 (s, 9H), 1.43 (s, 9H), 1.61ꢀ1.83 (m, 3H), 1.84ꢀ1.97
(m, 1H), 2.29ꢀ2.51 (m, 2H), 3.23ꢀ3.37 (m, 1H), 3.38ꢀ3.72 (2 m,
2H), 3.88ꢀ4.07 (m, 1H); 13C NMR (100 MHz, CDCl3) δ ꢀ4.9, ꢀ4.8,
14.4, 17.8, 25.5 (3C), 28.4 (3C), 29.4, 31.9, and 32.6 (rotamers), 44.1
and 44.6, 65.2 and 65.3, 74.9 and 75.4, 79.4 and 80.0, 119.2 and 119.6,
155.1, and 155.6. MS (ESI, m/z): 377 (M þ Naþ, 100). Anal. Calcd for
C18H34N2O3Si: C, 60.97; H, 9.67; N, 7.90. Found: C, 60.88; H, 9.95;
N, 8.12.
(7S,7aR/S)-7-(tert-Butyldimethylsilyloxy)pyrrolizidin-3-one
(24a/b). Toa solution ofthe diastereomeric mixture of10a and 2-epi-10a
(203 mg, 0.51 mmol) in EtOAc (1.5 mL) was added a 2 N aqueous
solution of HCl (1.0 mL, 2.0 mmol). The reaction mixture was stirred at rt
for 2 h and concentrated under reduced pressure. The residue was
dissolved in EtOH/H2O (4.0 mL/2.0 mL), and K2CO3 (141 mg, 1.0
mmol) was added. The reaction mixture was stirred for 48 h, filtered, and
concentrated under reduced pressure. The residue was purified by flash
chromatography on silica gel (eluent: MeOH/CH2Cl2 1:10) to afford
(7S,7aS/R)-7-hydroxy-pyrrolizidin-3-ones 23a/23b as an inseparable
diastereomeric mixture (dr = 88:12, determined by integral of 1H NMR)
in a combined yield of 96%: white solid. IR (film) vmax 3279, 2981, 2894,
1659, 1441, 1369 cmꢀ1. MS (ESI, m/z): 164 (M þ Naþ, 100%).
(7S,7aR)-23a: A pure sample of 23a was obtained via silylated derivative
and the data are given in the subsequent section.
2-epi-10c (minor diastereomer): colorless oil; [R]20D þ10.6 (c 1.1,
CHCl3). IR (film) vmax 2956, 2931, 2853, 2245, 1697, 1392 cmꢀ1. 1H
NMR (400 MHz, CDCl3) δ 0.08 (s, 6H), 0.89 (s, 9H), 1.45 and 1.45 (2s
br, 9H), 1.70ꢀ1.88 (m, 2H), 1.94ꢀ2.15 (m, 2H), 2.36ꢀ2.54 (m, 2H),
3.23ꢀ3.45 (m, 2H), 3.73ꢀ3.88 (m, 1H), 4.23ꢀ4.40 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ ꢀ5.3, ꢀ5.0, 14.5, 18.0, 25.7 (3C), 28.5 (3C), 29.7,
31.9 and 32.1, 42.8 and 43.2, 58.4, 71.7 and 72.4, 79.7 and 80.3, 119.9 and
120.2, 154.6, and 155.1. MS (ESI, m/z): 377 (M þ Naþ, 100).
(2R/S,3S)-3-tert-Butyldimethylsilyloxy-1-tert-butyloxycar-
bonyl-2-[(2-ethyloxycarbonyl)ethyl]piperidine (21a and
2-epi-21a). Following the general procedure, the SmI2-mediated
coupling reaction of aza-hemiacetal 9 with ethyl acrylate afforded 21a
in 53% yield and 2-epi-21a in 18% yield (dr = 75:25). 21a (major
diastereomer): colorless oil; [R]20D ꢀ9.1 (c 1.0, CHCl3). IR (film) vmax
(7S,7aS)-23b (data read from spectrum of the diastereomeric
mixture): 1H NMR (400 MHz, CDCl3) δ 1.88ꢀ2.02 (m, 1H), 2.05ꢀ
2.46 (m, 4H), 2.56ꢀ2.68 (m, 1H), 3.00ꢀ3.09 (m, 1H), 3.50ꢀ
4.07 (m, 4H including OH); 13C NMR (100 MHz, CDCl3) δ 18.0,
34.5, 36.0, 39.4, 66.6, 69.0, 176.7.
2954, 2930, 2857, 1736, 1693, 1419, 1365, 1255 cmꢀ1 1H NMR
.
(400 MHz, CDCl3) δ 0.02 (s, 3H), 0.05 (s, 3H), 0.87 (s, 9H), 1.24
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The Journal of Organic Chemistry
ARTICLE
To a diastereomeric mixture of 23a/b (580 mg, 4.1 mmol), DMAP
(cat.), TBSCl (930 mg, 6.2 mmol), and imidazole (560 mg, 8.2 mmol)
was added anhydrous CH2Cl2 (25 mL). The reaction mixture was
stirred for 24 h, quenched with water (10 mL), and extracted with
CH2Cl2 (3 ꢁ 15 mL). The combined organic phases were washed with
brine, dried over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure. The residue was purified by flash chromatography on
silica gel to afford compound (7S,7aR)-24a (890 mg, yield 85%) and its
diastereomer (7S,7aS)-24b (82 mg, yield 8%) (dr = 91:9). (7S,7aR)-24a
(CH), 76.96 (CH). MS (ESI, m/z): 128 (M þ Hþ, 100). HRESIMS
calcd for [C14H27N2O2]þ (2 M þ Hþ): 255.2067; found: 255.2063
(8S,8aR)-8-Hydroxyindolizidin-3-one (26). To a solution of
21a (65 mg, 0.16 mmol) in EtOAc (1.0 mL) was added a 2 N aqueous
solution of HCl (0.35 mL, 0.70 mmol). The reaction mixture was stirred
at rt for 2 h and concentrated under reduced pressure. The residue
was dissolved in EtOH/H2O (2.0 mL/1.0 mL) and treated with K2CO3
(44 mg, 0.32 mmol). The reaction mixture was stirred for 5 h, filtered,
and concentrated under reduced pressure. The residue was purified by
flash chromatography on silica gel (eluent: MeOH/CH2Cl2 1:20) to
afford the known indolizidinone 2621 (13 mg, yield 52%) as a white wax:
[R]20D þ33.4 (c 0.4, CHCl3) (no rotation data given in ref 21). IR (film)
(major diastereomer): colorless oil; [R]20 þ38.1 (c 0.9, CHCl3). IR
D
(film) vmax 2955, 2930, 2857, 1704, 1408, 1257 cmꢀ1. 1H NMR (400
MHz, CDCl3) δ 0.01 (s, 6H), 0.81 (s, 9H), 1.61ꢀ1.75 (m, 1H),
1.78ꢀ1.92 (m, 1H), 2.07ꢀ2.18 (m, 1H), 2.19ꢀ2.38 (m, 2H), 2.58
(ddd, J = 8.3, 10.0, 16.6 Hz, 1H), 3.05ꢀ3.17 (m, 1H), 3.48ꢀ3.57 (m,
1H), 3.62 (ddd app. q, J = 6.8 Hz, 1H), 3.75 (ddd app. q, J = 6.8 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ ꢀ4.9 (CH3), ꢀ4.8 (CH3), 17.8 (C),
24.9 (CH2), 25.5 (3C, CH3), 34.1 (CH2), 35.5 (CH2), 39.7 (CH2), 67.3
(CH), 76.5 (CH), 174.9 (CO). MS (ESI, m/z): 256 (M þ Hþ, 100).
HRESIMS calcd for [C13H26NO2Si]þ (M þ Hþ): 256.1727; found:
256.1722.
1
vmax 3297, 2916, 2854, 1648, 1445, 1282 cmꢀ1. H NMR (400 MHz,
CDCl3) δ 1.35ꢀ1.52 (m, 2H), 1.72ꢀ1.92 (m, 2H), 2.05ꢀ2.15 (m, 1H),
2.26ꢀ2.42 (m, 3H), 2.44ꢀ2.61 (m, 2H), 3.14ꢀ3.30 (m, 2H),
4.00ꢀ4.08 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 22.3, 23.3, 30.2,
33.4, 39.3, 62.8, 73.2, 173.8. MS (ESI, m/z): 156 (M þ Hþ, 100).
(2R,3R,4R)-1-tert-Butyloxycarbonyl-3,4-bis(benzyloxy)-
2-(benzyloxymethyl)pyrrolidine (32). To a solution of (3S,4R,5R)-5-
benzyloxymethyl-1-(tert-butoxycarbonyl)-3,4-dibenzyloxy -pyrroli-
din-2-one (31)30 (1.00 g, 1.93 mmol) in MeOH (50 mL) was added
NaBH4 with vigorous stirring in two portions (220 mg, 5.79 mmol and
150 mg, 3.95 mmol) over 30 min at ꢀ13 °C. The reaction mixture was
stirred for 30 min before addition of NaHCO3 (10 mL) and brine
(10 mL). The mixture was extracted with CH2C12 (3 ꢁ 30 mL). The
combined organic phases were washed with brine (10 mL), dried over
anhydrous Na2SO4, filtered, and concentrated under reduced pressure.
The crude product 30 (980 mg, yield 98%) was obtained as a colorless
oil. Without further purification and following the general procedure,
the SmI2-mediated coupling reaction of aza-hemiacetal 30 with ethyl
acrylate afforded only the reduced product 32 in 60% yield as a
(7S,7aS)-24b (minor diastereomer): colorlessoil;[R]20D þ31.1 (c 1.0,
CHCl3) {lit.19 [R]20D þ32.81 (c 1.045, CHCl3)}. IR (film) vmax 2955,
2930, 2857, 1698, 1404, 1255 cmꢀ1. 1H NMR (400 MHz, CDCl3) δ 0.03
(s, 6H), 0.83 (s, 9H), 1.86ꢀ2.14 (m, 4H), 2.32 (ddd, J= 4.2, 10.3, 16.8Hz,
1H), 2.53 (ddd, J = 8.4, 8.4, 16.8 Hz, 1H), 3.00ꢀ3.10 (m, 1H), 3.50ꢀ3.63
(m, 1H), 3.74 (ddd, J = 2.7, 5.5, 8.1 Hz, 1H), 3.97ꢀ4.03 (m, 1H); 13C
NMR (100 MHz, CDCl3) δ ꢀ5.1 (CH3), ꢀ4.8 (CH3), 17.7 (C), 18.0
(CH2), 25.5 (3C, CH3), 34.0 (CH2), 36.1 (CH2), 39.7 (CH2), 66.5
(CH), 70.5 (CH), 177.0 (CO). MS (ESI, m/z): 256 (M þ Hþ, 100).
(7S,7aR)-7-Hydroxypyrrolizidin-3-one (23a). To a solution of
pyrrolizidinone (7S,7aR)-24a (257 mg, 1.0 mmol) in EtOAc (3.0 mL)
was added a 2 N HCl aqueous solution (2.0 mL, 4.0 mmol). The reaction
mixture was stirred at rt for 2 h and concentrated under reduced
pressure. The residue was purified by flash chromatography on silica
gel (eluent: MeOH/CH2Cl2 1:10) to afford compound 23a (132 mg,
yield 94%) as a white solid: mp 113ꢀ114 °C (MeOH/CH2Cl2 1:10);
colorless oil: [R]20 ꢀ32.0 (c 1.4, CHCl3). IR (film) vmax 3030,
D
2927, 1694, 1453, 1392, 1365, 1258, 1171, 1097 cmꢀ1
.
1H NMR
(400 MHz, CDCl3) δ 1.35ꢀ1.55 (2 m, 9H, 3CH3), 3.40ꢀ3.52 (m,
1H), 3.52ꢀ3.64 (m, 1H), 3.65ꢀ4.20 (m, 4H), 4.22 (m, 1H),
4.74ꢀ4.34 (m, 6H, 3 ꢁ PhCH2), 7.40ꢀ7.22 (m, 15H, Ph-H). 13C
NMR (100 MHz, CDCl3) δ 28.5 (3C), 50.4 and 51.3, 61.6 and 61.9,
68.6 and 69.0, 71.3, 73.1, 79.8, 80.5, 81.6, 83.1, 127.57, 127.62, 127.8,
127.9, 128.35, 128.43, 128.45, 137.7, 138.0, 138.6, 154.4, and 154.7.
HRESIMS calcd for [C31H37NO5Na]þ (M þ Naþ): 526.2564; found:
526.2560.
(2R/S,3S,4R,5R)-1-tert-Butyloxycarbonyl- 3,4-bis(benzyloxy)-
5-(benzyloxymethyl)-2-(pyridin-2-ylthio)pyrrolidine (33H/L).
To a mixture of the aza-hemiacetal 30 (980 mg, 1.89 mmol), CaCl2 (425
mg, 3.86 mmol), and 2-thiol-pyridine (322 mg, 2.90 mmol) in anhy-
[R]20 þ19.4 (c 1.0, CHCl3). IR (film) vmax 3279, 2981, 2894, 1659,
D
1441, 1369 cmꢀ1. 1H NMR (400 MHz, CDCl3) δ 1.71ꢀ1.85 (m, 1H),
1.89ꢀ2.01 (m, 1H), 2.18ꢀ2.29 (m, 1H), 2.29ꢀ2.41 (m, 2H), 2.64 (ddd,
J = 10.0, 10.0, 17.0 Hz, 1H), 3.12ꢀ3.23 (m, 1H), 3.58 (ddd, J = 7.6, 7.6,
11.8 Hz, 1H), 3.69 (s br, 1H, OH), 3.73 (ddd app. q, J = 7.0 Hz, 1H),
3.83ꢀ3.94 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 25.1 (CH2), 34.3
(CH2), 35.3 (CH2), 40.1 (CH2), 67.5 (CH), 75.6 (CH), 175.6 (CO).
MS (ESI, m/z): 164 (M þ Naþ, 100). HRESIMS calcd for
[C7H11NO2Na]þ (M þ Naþ): 164.0682; found: 164.0677.
(1S,7aR)-1-Hydroxypyrrolizidine (25). To a suspension of
LAH (114 mg, 3.0 mmol) in anhydrous THF (10 mL) was added a
solution of pyrrolizidinone 23a (141 mg, 1.0 mmol) in THF (3.0 mL) at
0 °C. The reaction was warmed to 40ꢀ50 °C and stirred overnight. The
reaction was quenched by successive and careful addition of H2O
(0.12 mL), 15% NaOH (0.24 mL), and H2O (0.12 mL) at ꢀ10 °C.
The resulting mixture was filtered through Celite, washed with EtOAc
(5.0 mL), and the filtrate was concentrated under reduced pressure. The
residue was purified by flash chromatography on silica gel (eluent:
MeOH/CH2Cl2/ NH3 aq. 4:6:1) to afford pyrrolizidine 25 (77 mg, 60%
drous CH2Cl2 (30 mL) was added dropwise BF3 Et2O (0.24 mL, 1.93
3
mmol) under nitrogen atmosphere at 0 °C. The mixture was stirred for
1 h and allowed to warm to room temperature. After stirring at rt for
another 3 h, the reaction was quenched with a saturated aqueous
solution of NaHCO3 (20 mL). The aqueous layer was extracted with
CH2Cl2 (4 ꢁ 30 mL). The combined organic phase was washed with
brine, dried over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure. The residue was purified by flash chromatography on
silica gel (eluent: EtOAc/PE 1:8) to afford 33H (295 mg, yield 25.5%)
and its diastereomer 33L (688 mg, yield 59.5%) (dr = 30:70). 33H
(minor and less polar diastereomer): colorless oil; [R]20D þ53.1 (c 1.13,
CHCl3). IR (film) vmax 3030, 2975, 2927, 2864, 1698, 1578, 1453, 1415,
yield) as a pale yellow oil: [R]20 þ22.5 (c 0.6, CHCl3) {for the
D
antipode, lit. [R]20 ꢀ26 (c 2.3, CHC13);20a [R]20 ꢀ31.6 (c 0.5,
D
D
CHC13)20b}. IR (film) vmax 3345, 2924, 2965, 1445, 1327, 1160 cmꢀ1
.
1383, 1365, 1120, 1101 cmꢀ1 1H NMR (400 MHz, CDCl3) δ
.
1H NMR (400 MHz, CDCl3) δ 1.37ꢀ1.50 (m, 1H), 1.73ꢀ1.95 (m,
3H), 1.95ꢀ2.17 (m, 2H), 2.60 (ddd, J = 6.7, 8.0, 11.3 Hz, 1H), 2.74
(ddd, J = 4.7, 7.1, 11.3 Hz, 1H), 3.28 (ddd, J = 5.6, 5.6, 11.2 Hz, 1H), 3.44
(ddd, J = 6.6, 8.8, 11.2 Hz, 1H), 3.62 (ddd, J = 2.0, 7.8, 7.8 Hz, 1H),
4.05ꢀ4.12 (m, 1H), 4.98 (s br, 1H); 13C NMR (100 MHz, CDCl3)
δ 25.6 (CH2), 30.2 (CH2), 33.7 (CH2), 52.6 (CH2), 55.2 (CH2), 72.7
1.04ꢀ1.40 (2 m, 9H), 3.42ꢀ3.55 (m, 1H), 3.68ꢀ3.95 (m, 1H),
4.00ꢀ4.25 (m, 2H), 4.33 (s, 1H), 4.34ꢀ4.85 (m, 6H), 6.24ꢀ6.42
(2 m, 1H), 6.85ꢀ6.92 (m, 1H), 7.05ꢀ7.15 (m, 1H), 7.15ꢀ7.32
(m, 15H), 7.35ꢀ7.45 (m, 1H), 8.35ꢀ8.42 (m, 1H); 13C NMR (100
MHz, CDCl3) δ 27.9 and 28.4 (3C), 63.2 and 63.6, 65.7 and 66.0, 68.2,
70.8, 71.5, 73.0, 80.5 and 80.6, 81.6, 83.2, 85.9, 87.5, 119.4, 122.4 and 122.9,
4959
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The Journal of Organic Chemistry
ARTICLE
127.4, 127.5, 127.57, 127.62, 127.7, 128.3, 128.4, 135.9, 137.8, 137.9, 138.3,
pyrrolizidinone 27 (60 mg, 0.13 mmol) in THF (2.0 mL) at 0 °C under
an argon atmosphere. The reaction mixture was refluxed for 5 h and
quenched by successive and careful addition of H2O (0.5 mL), 15%
NaOH (0.5 mL), and H2O (0.5 mL) at ꢀ10 °C. After 1 h of stirring,
solid Na2SO4 was added, and the mixture was stirred for another 1 h.
The mixture was filtered through Celite and washed with EtOAc, and the
filtrate was concentrated under reduced pressure. The residue was
purified by chromatography on silica gel (eluent: EtOAc/PE 1:2ꢀ1:1)
to give 34 (46 mg, yield 79%) as a white solid: mp 48ꢀ49 °C (EtOAc/
PE 1:1) (lit.24h mp 48ꢀ49 °C); [R]20D ꢀ2.9 (c 0.7, CHCl3) {[R]20D ꢀ5
(c 1, CHCl3);24d [R]20D ꢀ2.9 (c 0.7, CHCl3)24h}. IR (film) vmax 3030,
2864, 1496, 1454, 1365, 1206, 1113, 1028 cmꢀ1. 1H NMR (400 MHz,
CDCl3) δ 1.47ꢀ1.58 (m, 1H), 1.60ꢀ1.70 (m, 1H), 1.70ꢀ1.82 (m, 1H),
1.82ꢀ1.92 (m, 1H), 2.66 (ddd, J = 6.6, 6.7, 10.6 Hz, 1H), 2.85 (ddd, J =
4.6, 5.8, 7.3 Hz, 1H), 2.94 (ddd, J = 6.0, 6.2, 10.6 Hz, 1H), 3.36 (ddd,
J = 5.9, 6.8, 6.9 Hz, 1H), 3.42 (dd, J = 5.8, 9.6 Hz, 1H), 3.49 (dd, J =
4.6, 9.6 Hz, 1H), 3.70 (dd, J = 5.9, 6.1 Hz, 1H), 3.97 (dd, J = 6.1, 7.3 Hz,
1H), 4.39ꢀ4.61 (m, 6H), 7.11ꢀ7.29 (m, 15H, Ph-H); 13C NMR (100
MHz, CDCl3) δ 25.7 (CH2), 31.5 (CH2), 55.0 (CH2), 67.3 (CH), 68.2
(CH), 71.7 (CH2), 72.0 (CH2), 72.4 (CH2), 73.1 (CH2), 85.6 (CH),
88.7 (CH), 127.3 (CH), 127.4 (CH), 127.5 (CH), 127.6 (CH), 128.1
(CH), 128.2 (CH), 128.3 (CH), 138.1 (C), 138.35 (C), 138.39 (C). MS
(ESI, m/z): 444 (M þ Hþ, 100). HRESIMS calc for [C29H34NO3]þ
(M þ Hþ): 444.2533; found: 444.2531.
138.6, 149.2, 153.9, 159.5. MS (ESI, m/z): 613 (M þ Hþ, 100).
33L (major and more polar diastereomer): colorless oil; [R]20
ꢀ
D
160 (c 1.1, CHCl3). IR (film) vmax 3030, 2924, 2863, 1705, 1578, 1454,
1
1415, 1210, 1124, 1186, 1070 cmꢀ1. H NMR (400 MHz, CDCl3)
δ 1.05ꢀ1.42 (m, 9H), 3.52ꢀ3.88 (m, 3H), 4.20ꢀ4.30 (m, 2H),
4.32ꢀ4.71 (m, 6H), 6.75ꢀ6.80 (m, 1H), 6.88ꢀ6.92 (m, 1H),
7.05ꢀ7.32 (m, 15H), 7.32ꢀ7.42 (m, 1H), 8.35ꢀ8.45 (m, 1H); 13C
NMR (100 MHz, CDCl3) δ 28.1 (3C), 60.5, 72.7, 73.3, 80.6, 82.7, 119.9,
123.8, 127.4, 127.55, 127.63, 127.7, 127.8, 128.0, 128.3, 136.0,
137.7, 138.4, 149.3, 153.2. MS (ESI, m/z): 613 (M þ Hþ, 100).
HRESIMS calcd for [C36H41N2O5S]þ (M þ Hþ): 613.2731; found:
613.2723.
(2R,3R,4R,5R)-1-tert-Butyloxycarbonyl 3,4-bis(benzyloxy)-2-
(benzyloxymethyl)-5-[(2-ethyloxycarbonyl)ethyl]pyrrolidine
(29). To a solution of the diastereomeric mixture 33H/L (200 mg, 0.33
mmol), ethyl acrylate (0.08 mL, 0.65 mmol), and BF3 Et2O (0.08 mL,
3
0.65 mmol) in anhydrous THF (10 mL) was added dropwise a freshly
prepared t-BuOH-containing SmI2 (13 mL, 1.30 mmol) at ꢀ60 °C.
The reaction mixture was stirred for 30 min and quenched with a
saturated aqueous solution of NH4Cl (10 mL). The aqueous layer was
extracted with EtOAc (3 ꢁ 15 mL). The combined organic phases were
washed with brine, dried over anhydrous Na2SO4, filtered, and concen-
trated under reduced pressure. The residue was purified by flash
chromatography on silica gel (eluent: EtOAc/PE 1:6) to afford 29
(120 mg, yield 61%) as a colorless oil: [R]20D ꢀ36.4 (c 1.1, CHCl3). IR
(film) vmax 2977, 2931, 2864, 1734, 1693, 1454, 1391, 1366, 1255, 1175,
1096, 1028 cmꢀ1. 1H NMR (400 MHz, CDCl3): δ 1.11ꢀ1.18 (m, 3H),
1.25ꢀ1.45 (2 m, 9H) 1.81ꢀ1.98 (m, 1H), 2.02ꢀ2.33 (m, 3H),
3.33ꢀ3.43 (m, 1H), 3.61ꢀ4.18 (m, 7H), 4.22ꢀ4.60 (m, 6H),
7.07ꢀ7.30 (m, 15H, Ph-H); 13C NMR (100 MHz, CDCl3) δ 14.2,
26.1, 27.2, 28.4, and 28.5 (3C), 31.7, 60.4, 62.6 and 62.8, 63.8 and 63.9,
67.9, 68.7, 70.98, 71.04, 71.2, 73.0, 77.4, 79.8 and 79.9, 81.6, 83.0, 83.6,
84.8, 127.47, 127.52, 127.6, 127.7, 127.8, 128.3, 128.4, 128.5, 137.7,
137.9, 138.3, 138.7, 153.8 and 154.0, 172.9, and 173.0. MS (ESI, m/z):
626 (M þ Naþ, 100). Anal. Calcd for C36H45NO7: C, 71.62; H, 7.51; N,
2.32. Found: C, 71.21; H, 7.40; N, 2.66.
Hyacinthacine A2 (2). To a solution of pyrrolizidine 34 (120 mg,
0.28 mmol) in methanol (10 mL) was added Pd/C 10% (50 mg). After
purging with hydrogen, 10 drops of HCl (6 N) were added. The
suspension was stirred for 4 days at room temperature under 1 atm of
hydrogen. The mixture was filtered through Celite and washed with
MeOH. The filtrate was neutralized with DOWEX 1 ꢁ 8 resin (OHꢀ
form) and filtered. The filtrate was concentrated under reduced pres-
sure to give hyacinthacine A2 (2) (38 mg, yield 81%) as a colorless oil:
[R]20 þ10.6 (c 1.64, H2O) {[R]25 þ12.5 (c 0.4, H2O);24a [R]25
D
D
D
þ12.7 (c 0.13, H2O);24b [R]25D þ10.5 (c 0.6, H2O);24c [R]20D þ11.2
(c 0.52, H2O)24e}. IR (film) vmax 3354, 2956, 2920, 2866, 1124 cmꢀ1. 1H
NMR (400 MHz, D2O) δ 1.67ꢀ1.96 (m, 4H), 2.66 (ddd, J = 3.9, 6.6,
9.0 Hz, 1H), 2.70 (td, J = 5.6, 11.0Hz, 1H), 2.86 (ddd, J = 5.9, 7.1, 11.0 Hz,
1H), 3.11 (td, J = 4.4, 7.4 Hz, 1H), 3.61 (dd, J = 6.6, 11.6 Hz, 1H),
3.66ꢀ3.77 (m, 3H); 13C NMR (100 MHz, D2O) δ 27.3 (CH2), 32.6
(CH2), 57.6 (CH2), 65.9 (CH2), 68.8 (CH), 71.9 (CH), 80.1 (CH),
83.0 (CH). HRESIMS calcd for [C8H16NO3]þ (M þ Hþ): 174.1125;
found: 174.1130.
(5R,6R,7R,7aR)-6,7-Bis(benzyloxy)-5-(benzyloxymethyl)-
pyrrolizidin-3-one (27). To a solution of pyrrolidine 29 (250 mg,
0.41 mmol) in EtOAc (2.0 mL) was added a 2 N aqueous solution of
HCl (2.0 mL, 4.0 mmol) at 0 °C, and the reaction mixture was stirred for
30 min. After warming to rt, the reaction mixture was stirred for another
2 h and concentrated under reduced pressure. The residue was dissolved
in MeOH/H2O (3.0 mL/1.5 mL), and K2CO3 (300 mg, 2.2 mmol) was
added. The mixture was stirred for 2 days, filtered, and concentrated
under reduced pressure. The residue was purified by flash chromatog-
raphy on silica gel (eluent: EtOAc/PE 1:1.5) to afford compound 27
(165 mg, yield 87%) as a colorless oil: [R]20D ꢀ25.6 (c 1.2, CHCl3). IR
(5R,6R,7R,7aR)-6,7-Bis(benzyloxy)-5-(benzyloxymethyl)-
[5,6,7,7a]-tetrahydropyrrolizin-3-one (28). To a stirring solu-
tion of LDA (0.48 mmol) in THF (1.0 mL) [prepared by adding a
solution of 2.5 N n-BuLi in n-hexane (0.19 mL, 0.48 mmol) to i-Pr2NH
(0.075 mL, 0.53 mmol)] was added dropwise a solution of pyrrolizidi-
none 27 (100 mg, 0.22 mmol) in THF (1.0 mL) over 5 min under N2
atmosphere at ꢀ78 °C. After 10 min of stirring, a solution of PhSeBr
(57 mg, 0.24 mmol) in THF (1.0 mL) was added rapidly. The mixture
was stirred for 30 min and quenched with a saturated aqueous solution of
NaHCO3 (1.0 mL). The aqueous layer was extracted with EtOAc (3 ꢁ
10 mL). The combined organic phases were washed with brine, dried
over Na2SO4, filtered, and concentrated under reduced pressure. The
residue was dissolved in CH2Cl2 (6.0 mL), and H2O2 (30%) was added
dropwise until the phenylselenylated intermediate disappeared. The
reaction was quenched with H2O (10 mL). The aqueous layer was
extracted with CH2Cl2 (3 ꢁ 10 mL). The combined organic phases were
washed with brine, dried over Na2SO4, filtered, and concentrated under
reduced pressure. The residue was purified by flash chromatography on
silica gel (eluent: EtOAc/PE 2:3) to afford compound 28 (71 mg, yield
71%) as a colorless oil and recovered starting material 27 (10 mg, 10%):
(film) vmax 3030, 2864, 1693, 1454, 1411, 1364, 1313, 1105, 1028 cmꢀ1
.
1H NMR (400 MHz, CDCl3) δ 1.75 (dddd, J = 7.3, 9.8, 10.0, 12.0 Hz,
1H), 2.17 (dddd, J = 2.3, 7.3, 10.0, 12.0 Hz, 1H), 2.28 (ddd, J = 2.3, 9.8,
16.8 Hz, 1H), 2.51 (ddd, J = 10.0, 10.0, 16.8 Hz, 1H), 3.47 (dd, J = 4.3,
9.7 Hz, 1H), 3.56 (dd, J = 5.6, 9.7 Hz, 1H), 3.63 (dd, J = 4.8, 7.3 Hz, 1H),
3.82 (ddd app. q, J = 7.3 Hz, 1H), 3.99 (ddd, J = 4.2, 4.3, 5.6 Hz, 1H),
4.24 (dd, J = 4.2, 4.8 Hz, 1H), 4.38ꢀ4.55 (m, 6H), 7.17ꢀ7.30 (m, 15H);
13C NMR (100 MHz, CDCl3) δ 25.8 (CH2), 33.3 (CH2), 58.6
(CH), 63.8 (CH), 69.4 (CH2), 72.2 (CH2), 72.4 (CH2), 73.3 (CH2),
87.1 (CH), 89.2 (CH), 127.66 (CH), 127.69 (CH), 127.8 (CH),
127.90 (CH), 127.92 (CH), 128.39 (CH), 128.4 (CH), 128.5
(CH), 137.8 (C), 137.9 (C), 138.0 (C), 174.8 (CO). MS (ESI, m/z):
458 (M þ Hþ, 100).
(1R,2R,3R,7aR)-1,2-Bis(benzyloxy)-3-(benzyloxymethyl)-
pyrrolizidine (34). To a suspension of LAH (9 mg, 0.25 mmol)
in anhydrous THF (3.0 mL) was added dropwise a solution of
[R]20 þ45.6 (c 1.4, CHCl3). IR (film) vmax 3062, 3029, 2864, 1692,
D
1461, 1360, 1098, 1028 cmꢀ1. 1H NMR (400 MHz, CDCl3) δ 3.57 (dd,
4960
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The Journal of Organic Chemistry
ARTICLE
J = 6.4, 8.2 Hz, 1H), 3.64 (dd, J = 3.8, 9.9 Hz, 1H), 3.70 (dd, J = 5.0,
9.9 Hz, 1H), 3.97ꢀ4.03 (m, 1H), 4.28 (d, J = 8.2 Hz, 1H), 4.72ꢀ4.76
(m, 7H), 6.06 (dd, J = 1.5, 5.8 Hz, 1H), 6.96 (dd, J = 1.8, 5.8 Hz, 1H),
7.45- 7.25 (m, 15H, Ph-H); 13C NMR (100 MHz, CDCl3) δ 58.4 (CH),
68.8 (CH), 70.2 (CH2), 72.6 (CH2), 73.1 (CH2), 73.3 (CH2), 85.8
(CH), 88.9 (CH), 127.6 (CH), 127.7 (CH), 127.8 (CH), 128.1 (CH),
128.3 (CH), 128.5 (CH), 137.4 (C), 137.8 (C), 137.9 (C), 147.4 (CH),
174.2 (CO). HRESIMS calcd for [C29H30NO4]þ (M þ Hþ): 456.2169;
found: 456.2167.
silica gel (eluent: EtOAc/PE 3:1) to afford diastereomer 35 (6 mg, 9%)
as a white wax, and diastereomer 36 (35 mg, 55%) as a white solid.
(ꢀ)-Uniflorine A (3). To a suspension of LAH (3.8 mg, 0.1 mmol)
in anhydrous THF (1.0 mL) was added a solution of compound 35
(20 mg, 0.04 mmol) in THF (1.0 mL) at 0 °C under an argon
atmosphere. The reaction mixture was refluxed for 5 h and quenched
by successive and careful addition of H2O (0.1 mL), 15% NaOH
(0.1 mL), and H2O (0.3 mL) at ꢀ10 °C. After stirring for 20 min,
Na2SO4 was added, and the resulting mixture was stirred for 1 h. The
mixture was filtered through Celite and washed with EtOAc (2.0 mL),
and the filtrate was concentrated under reduced pressure. The residue
was dissolved in MeOH (1.0 mL), and PdCl2 (11 mg, 0.06 mmol) was
added. The mixture was stirred at rt under 1 atm of hydrogen for 12 h,
filtered through Celite, washed with MeOH, and concentrated under
reduced pressure. The residue was dissolved in water, washed with CH2Cl2
(2 ꢁ 2.0 mL), and purified through a column of Amberlyst (OHꢀ) A-26
resin (eluent: H2O) to afford uniflorine A (3) (6.5 mg, yield 78%) as a white
solid:mp177ꢀ180°C(MeOH) (mp174ꢀ178°C;25 mp177ꢀ180°C27b);
[R]20D ꢀ6.7 (c 0.42, H2O) {lit.27b [R]21D ꢀ6.9 (c 0.415, H2O)}. IR (film)
(1S/R,2S/R,5R,6R,7R,7aR)-6,7-Bis(benzyloxy)-5-(benzyloxy-
methyl)-1,2-dihydroxypyrrolizidin-3-one (35 and 36). Dihy-
droxylation with OsO4/NMO. To a stirring solution of R,β-unsaturated
pyrrolizidinone 28 (70 mg, 0.15 mmol) in tert-butyl alcohol/water (1:1,
2.0 mL) were added 4-methylmorpholine N-oxide (20 mg, 0.17 mmol),
citric acid (32 mg, 0.15 mmol), and OsO4 (0.01 mL, 2 mM in water, 0.02
mmol). The reaction mixture was stirred at rt for 24 h (the color changed
from bright green to a pale yellow). The reaction was quenched with a
saturated aqueous solution of Na2SO3 (2.0 mL) and extracted with
EtOAc (3 ꢁ 10 mL). The combined organic phases were washed with
brine, dried over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure. The residue was purified by flash chromatography on
silica gel (eluent: EtOAc/PE 3:1) to afford compound 35 (42 mg, yield
56%) and its diastereomer 36 (28 mg, yield 37%) (dr = 60:40).
v
max 3374, 2963, 2909, 2847, 1379, 1262, 1092, 1022 cmꢀ1. 1H NMR (400
MHz, D2O) δ 2.76 (m, 1H), 2.98 (dd, J = 5.3, 12.0 Hz, 1H), 3.04 (dd, J =
5.6, 12.0 Hz, 1H), 3.14 (dd, J = 4.8, 7.5 Hz, 1H), 3.62 (dd, J = 6.5, 11.7 Hz,
1H), 3.77 (dd, J = 3.7, 11.7 Hz, 1H), 3.79 (dd, J = 8.3, 8.3 Hz, 1H), 3.94 (dd,
J = 7.5, 8.3 Hz, 1H), 4.18 (dd, J = 4.8, 4.8 Hz, 1H), 4.36 (ddd, J = 4.8, 5.3, 5.6
Hz, 1H); 13C NMR (100 MHz, D2O) δ 57.8 (CH2), 63.1 (CH2), 70.4
(CH), 71.5 (CH), 72.1 (CH), 75.9 (CH), 77.8 (CH), 79.1(CH). MS
(ESI m/z): 206 (M þ Hþ, 100%). HRESIMS calcd for [C8H16NO5]þ
(M þ Hþ): 206.1023; found: 206.1024.
Compound 35 (major diastereomer): white wax; [R]20 ꢀ51.1 (c 1.0,
D
CHCl3). IR (film) vmax 3333, 2993, 2950, 1678, 1462, 1366, 1261, 1115,
1028 cmꢀ1. 1H NMR (400 MHz, CDCl3) δ 3.35 (d, J = 9.0 Hz, 1H), 3.54
(dd, J = 4.6, 9.8 Hz, 1H), 3.61 (dd, J = 6.2, 9.8 Hz, 1H), 3.82ꢀ3.88 (m,
2H), 4.01ꢀ4.09 (m, 2H), 4.20 (d, J = 6.0 Hz, 1H), 4.27ꢀ4.32 (m, 1H),
4.46 (d, J= 12.0 Hz, 1H), 4.53 (d, J= 12.0 Hz, 1H), 4.54 (s, 2H), 4.56 (d, J=
11.8 Hz, 1H), 4.73 (d, J = 11.8 Hz, 1H), 5.17 (s br, 1H), 7.42- 7.22 (m,
15H, Ph-H); 13C NMR (100 MHz, CDCl3) δ 58.9 (CH), 68.3 (CH2),
71.0 (CH), 71.9 (CH2), 72.0 (CH), 72.1 (CH2), 73.2 (CH), 73.3 (CH2),
86.2 (CH), 86.4 (CH), 127.6 (CH), 127.7 (CH), 127.83 (CH), 127.86
(CH), 127.9 (CH), 128.4 (CH), 128.5 (CH), 137.4 (C), 137.6 (C), 137.8
(C), 172.5 (CO). MS (ESI, m/z): 512 (M þ Naþ, 100). HRESIMS calcd
for [C29H32NO6]þ (M þ Hþ): 490.2224; found: 490.2239.
7-epi-Casuarine (7-epi-Uniflorine B) (37). To a suspension of
LAH (3.8 mg, 0.1 mmol) in anhydrous THF (1.0 mL) was added a
solution of compound 36 (20 mg, 0.04 mmol) in THF (1.0 mL) at
0 °C under an argon atmosphere. The reaction mixture was refluxed
for 5 h and quenched by successive and careful addition of H2O
(0.1 mL), 15% NaOH (0.1 mL), and H2O (0.3 mL) at ꢀ10 °C. After
20 min of stirring, Na2SO4 was added, and the resulting mixture was
stirred for 1 h. The mixture was filtered through Celite and washed
with EtOAc (2.0 mL), and the filtrate was concentrated under reduced
pressure. The residue was dissolved in MeOH (1.0 mL), and PdCl2 (11
mg, 0.06 mmol) was added. The mixture was stirred at rt under 1 atm of
hydrogen for 12 h. The mixture was filtered through Celite and
washed with MeOH, and the filtrate was concentrated under reduced
pressure. The residue was dissolved in water, washed with CH2Cl2
(2 ꢁ 2.0 mL), and purified through a column of Amberlyst (OHꢀ)
A-26 resin (eluent: H2O) to afford 7-epi-casuarine (37) (5 mg, yield
60%) as a white wax: [R]20D þ6.1 (c 0.62, H2O) {lit.35 [R]22D þ6.2
(c 0.65, H2O)}. IR (film) νmax 3443, 2916, 1260, 1092, 1020 cmꢀ1. 1H
NMR (400 MHz, D2O) δ 2.60 (dd app. t, J = 9.8, 9.8 Hz, 1H),
2.79 (ddd, J = 3.5, 6.6, 9.9 Hz, 1H), 3.23 (dd, J = 4.2, 8.0 Hz, 1H), 3.26
(dd, J = 6.5, 9.8 Hz, 1H), 3.58 (dd, J = 6.6, 11.8 Hz, 1H), 3.78 (dd, J =
3.5, 11.8 Hz, 1H), 3.84 (dd, J = 8.0, 9.9 Hz, 1H), 4.14 (dd, J = 3.9,
4.2 Hz, 1H), 2.79 (ddd, J = 3.9, 6.5, 9.8 Hz, 1H), 4.37 (dd, J = 8.0,
8.0 Hz, 1H); 13C NMR (100 MHz, D2O) δ 56.8 (CH2), 63.3 (CH2),
69.0 (CH), 70.6 (CH), 71.6 (CH), 73.9 (CH), 74.1 (CH), 78.6(CH).
HRESIMS calc for [C8H15NO5Na]þ (M þ Naþ): 228.0842; found:
228.0840.
Compound 36 (minor diastereomer): white solid; mp 103ꢀ105 °C
(EtOAc/PE 3:1); [R]20 ꢀ2.5 (c 1.0, CHCl3). IR (film) vmax 3345,
D
2993, 2922, 2851, 1688, 1453, 1378, 1130, 1083 cmꢀ1. 1H NMR (400
MHz, CDCl3) δ 2.60 (s br, 1H), 3.25 (s br, 1H), 3.52 (dd, J = 4.0, 9.9 Hz,
1H), 3.61 (dd, J = 5.3, 9.9 Hz, 1H), 3.83 (dd, J = 3.5, 6.3 Hz, 1H), 4.03
(dd, J = 4.6, 9.1 Hz, 1H), 4.27ꢀ4.42 (m, 4H), 4.27ꢀ4.32 (m, 1H), 4.45
(d, J = 12.0 Hz, 1H), 4.51 (d, J = 12.0 Hz, 1H), 4.54ꢀ4.67 (m, 4H,
PhCH), 7.20ꢀ7.42 (m, 15H, Ph-H); 13C NMR (100 MHz, CDCl3)
δ 58.6 (CH), 65.4 (CH), 68.2 (CH2), 69.4 (CH), 72.4 (CH2), 72.8
(CH2), 73.2 (CH2), 73.4 (CH), 80.7 (CH), 84.3 (CH), 127.65 (CH),
127.71 (CH), 127.8 (CH), 127.9 (CH), 128.0 (CH), 128.38 (CH),
128.41 (CH), 128.44 (CH), 137.6 (C), 137.86 (C), 137.9 (C), 172.9
(CO). MS (ESI, m/z): 512 (M þ Naþ, 100). HRESIMS calcd for
[C29H32NO6]þ (M þ Hþ): 490.2224; found: 490.2228.
Dihydroxylation with KMnO4/18-crown-6. A solution of R,β-unsa-
turated pyrrolizidinone 28 (60 mg, 0.13 mmol) and 18-crown-6 (8.7 mg,
0.033 mmol) in DCM (0.8 mL) was cooled to ꢀ10 °C. Next, 12.5 mg
(0.08 mmol) of powdered KMnO4 was added in one portion, and
the dark mixture was stirred briskly. After 3 h, an additional 12.5 mg
(0.08 mmol) of powdered KMnO4 was added in one portion. After
being stirred for 13 h, the reaction was quenched at ꢀ10 °C by addition
of 1.0 mL of saturated aqueous Na2SO3 while stirring briskly. The
cooling bath was removed, and a saturated aqueous solution of citric acid
added dropwise until the brown color disappeared. After 5.0 mL of
DCM was added, the organic phase was separated. The aqueous phase
was extracted with DCM (3 ꢁ 5.0 mL). The combined organic phases
were dried over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure. The residue was purified by flash chromatography on
’ ASSOCIATED CONTENT
Supporting Information. 1H and 13C NMR spectra of all
S
b
new compounds; H1ꢀH1 COSY and NOESY spectra of com-
pounds 34 and 38. This material is available free of charge via the
Internet at http://pubs.acs.org.
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The Journal of Organic Chemistry
ARTICLE
’ AUTHOR INFORMATION
Flowers, R. A., II; Procter, D. J. J. Am. Chem. Soc. 2009, 131, 15467–15473.
(k) Parmar, D.; Price, K.; Spain, M.; Matsubara, H.; Bradley, P. A.; Procter,
D. J. J. Am. Chem. Soc. 2011, 133, 2418–2420.
Corresponding Author
*E-mail: zxiao@xmu.edu.cn; pqhuang@xmu.edu.cn.
(9) For selected methods on the SmI2-mediated R-amino CꢀC
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41, 1772–1775. (c) Masson, G.; Cividino, P.; Py, S.; Vallꢀee, Y. Angew.
Chem., Int. Ed. 2003, 42, 2265–2268. (d) Riber, D.; Skrydstrup, T. Org.
Lett. 2003, 5, 229–231. (e) Blakskjær, P.; Gavrila, A.; Andersen, L.;
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’ ACKNOWLEDGMENT
The authors are grateful to the NSF of China (20402012;
20832005), the National Basic Research Program (973
Program) of China (Grant No. 2010CB833200), and the Natural
Science Foundation of Fujian Province of China (No.
2010J01050) for financial support.
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